A childhood acute lymphoblastic leukemia-specific lncRNA implicated in prednisolone resistance, cell proliferation, and migration

Abstract

Childhood acute lymphoblastic leukemia (cALL) is the most common pediatric cancer and, despite an 85% cure rate, still represents a major cause of disease-related death in children. Recent studies have implicated long non-coding RNAs (lncRNAs) in cALL etiology, progression, and treatment response. However, barring some exceptions little is known about the functional impact of lncRNAs on cancer biology, which limits their potential as potential therapeutic targets. We wanted to investigate the functional role of lncRNAs identified as specifically overexpressed in pre-B cALL by whole-transcriptome sequencing. Here we report five lncRNAs specifically upregulated in pre-B cALL that had significant impacts on cancer hallmark traits such as cell proliferation, migration, apoptosis, and treatment response. In particular, silencing of the RP11-137H2.4 lncRNA effectively restored normal glucocorticoid (GC) response in a GC-resistant pre-B cALL cell line and specifically modulated expression of members of both the NRAS/BRAF/NF-?B MAPK cascade and cell cycle pathways. Since GC form the cornerstone of cALL chemotherapy and resistance in cALL confers a dismal prognosis, characterizing RP11-137H2.4sexact role and function in this process will be critical to the development of new therapeutic approaches to overcome GC resistance in children treated for cALL.

lncRNAs–mRNAs Co–Expression Network Underlying Childhood B–Cell Acute Lymphoblastic Leukaemia: A Pilot Study

“…Indeed, several lncRNA signatures for different tumours such as large–B–cell lymphoma, ovarian cancer, breast cancer and other oncological diseases have been reported [ 12 , 13 , 14 , 37 , 58 , 59 , 60 , 61 , 62 ]. However, few B–ALL–related lncRNAs have been characterized by their functional roles [ 15 , 52 ] and the lncRNA’s involvement in B–ALL development and/or progression as well as how they may orchestrate the B–ALL transcriptome landscape along with the protein–coding genes (PCGs) is far to be fully elucidated. In this context, we attempted to fill this knowledge gap by exploiting the transcriptome dataset already published by our research group [ 33 ] (Bioproject: PRJNA601326) for evaluating possible functional cooperation of lncRNAs with mRNAs.…”

“…Several aberrantly expressed lncRNAs have been found associated with B–ALL [ 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 ]. For instance, Fernando et al [ 19 ] highlighted the over–expression of the lncRNA CASC15 with regulatory roles on the transcriptional factor SOX4, in paediatric RUNX–1 translocated B–ALL.…”

“…Moreover, lncRNAs BALR–2 and BALR–6 have tumour–suppressor potential promoting cell survival in B–ALL and cell lines [ 18 ]. Another lncRNA, RP11–137H2.4 possesses tumour suppressor activity; indeed, in vitro in human pre–B–cell lines, silencing, has a strong impact on cell proliferation, migration and apoptosis [ 15 ].…”

Drug Resistance Biomarkers and Their Clinical Applications in Childhood Acute Lymphoblastic Leukemia

“…In particular, knockout of lncRNA RP11-137H2.4 effectively involves in inhibition of cell proliferation and migration and sensitive GC-resistant BCP-ALL cells to GC. This lncRNA has prognostic role and can be critical for the development of novel therapies to put an end to GC resistance in childhood BCP-ALL (116).…”

LncRNAs downregulated in childhood acute lymphoblastic leukemia modulate apoptosis, cell migration, and DNA damage response

“…Indeed, the BALR-2 and BALR-6 lncRNAs were found to be involved in cell survival or glucocorticoid response in both human and mouse B cells [ 12 , 13 ]. Furthermore, we and others have demonstrated that lncRNA transcription profiles can discriminate pre-B cALL subtypes accurately [ 2 , 12 , 14 , 15 ] or can act as prognostic biomarkers [ 2 ]. Although the importance of lncRNAs in tumor biology is clear, little is known about their precise function.…”